A rare mutation may explain why some people with a high genetic Alzheimer’s risk stay sharp into their 80s

A rare mutation in a gene called FN1 may help explain why some people with the strongest common genetic risk for Alzheimer’s disease remain mentally sharp into their 80s. Columbia University researchers led by Caghan Kizil published the work in the journal Nature Aging on Sept. 11, 2026, and ScienceDaily carried a summary of the university’s announcement on Oct. 19, 2026.

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The gene variant at issue is APOE ε4, which the report says roughly one in five people carry in at least one copy. Carrying it raises risk but does not guarantee disease, and the new study points to a specific biological reason that some carriers escape. The finding is best read as a lead for drug research, not as advice for anyone who has had a genetic test: no treatment or prevention method follows from it yet, and the work has so far been described mainly through a university announcement and press coverage of it.

How APOE4 affects the blood-brain barrier

The study is titled “Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer’s disease,” and it appears in Nature Aging. According to the ScienceDaily summary of the release, APOE ε4 promotes the production of fibronectin and its buildup around blood vessels in the brain. In mice carrying APOE ε4, brain fibronectin was nearly twice that of mice carrying the more common APOE ε3 variant, and the animals showed signs of a leaky blood-brain barrier, the protective lining that controls what passes from blood into brain tissue.

Raising human fibronectin in astrocytes, the star-shaped support cells of the brain, disrupted the barrier, while lowering it improved barrier function. The team says the excess protein activates abnormal integrin and focal adhesion kinase signaling, which in turn disrupts growth factor signaling between astrocytes and blood vessel cells.

The rare FN1 mutation behind the protection

The protective mutation sits in FN1, the gene that makes fibronectin. Carriers of APOE ε4 who also have this rare FN1 mutation appear to be shielded from the harmful protein buildup, the report says. The earlier work that identified the variant was described by Being Patient, which reported that carriers of the variant had a 70% lower risk of Alzheimer’s, and that among carriers who did develop the disease, symptoms began about 3.4 years later on average. That earlier analysis used more than 10,000 healthy people over 70 with two copies of APOE4 drawn from two genetic databases, and roughly one in 50 of them carried the variant.

Kizil, a professor of neurological sciences at Columbia’s Vagelos College of Physicians and Surgeons and a researcher at the Taub Institute, said the new study moves the field from a genetic clue to a disease mechanism. Co-first author Prabesh Bhattarai, an associate research scientist in Kizil’s lab, said the animal experiments allowed the team to move beyond association. Together with co-first author Elanur Yilmaz, he worked on experiments in which changing fibronectin levels in cells and animals changed how well the barrier held up, which is the step that distinguishes a mechanism from a statistical link between a gene and a disease.

What the evidence does and does not show

Much of the mechanistic evidence comes from laboratory systems: human stem-cell models, three-dimensional blood vessel cultures, zebrafish and mice. The researchers also analyzed human brain tissue and cerebrospinal fluid, along with genetic and epigenetic data, and found that higher fibronectin was associated with astrocyte inflammation. Co-first author Elanur Yilmaz said the same biological pattern appeared across experimental models and human Alzheimer’s tissue. Badri Vardarajan, an associate professor at Columbia, said the convergence of independent human datasets strengthens the case. The summary does not report sample sizes for the human work, and those details sit in the full paper.

Because the human findings describe similar biological disturbances, they are associations and do not prove that the mutation causes the preserved memory. The mutation is also rare, so most APOE ε4 carriers would not have it, and the report gives no figure for how common it is. Anyone worried about their own genetic risk is better served by talking with a physician or genetic counselor than by drawing conclusions from a laboratory study. Richard Mayeux, chair of neurology at Columbia, said the study gives new therapeutic targets and potential ways to measure whether treatments are working. Those ideas, which include limiting fibronectin buildup and restoring growth factor signaling, remain in laboratory investigation.

Columbia’s own news release also carries a disclosure: Kizil, Richard Mayeux and Badri Vardarajan are founders and shareholders of KVM Therapeutics and are inventors on patent applications for approaches that target FN1, and Kizil also holds a stake in Neuron-D GmbH. Those interests do not change the experimental results, but readers weighing the commercial promise of fibronectin-targeting drugs should know they exist. A further caution comes from fibronectin’s ordinary job. The protein supports tissue structure and healing, so any therapy would need to reduce its harmful accumulation around brain vessels without interfering with those functions. The Deseret News coverage reached the same conclusion: the findings suggest possible treatment targets but do not establish a therapy or a way to prevent the disease.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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